Field of the Invention
The invention relates generally to p53 cancer mutants. More particularly, it relates to the use of small molecules to enhance p53 activity in p53 cancer mutants.
Related Art
1. Reactivation of p53 Cancer Mutants.
The tumor suppressor protein p53, called the “Guardian of the Genome,” controls several central cellular tumor suppressor pathways, including cell cycle arrest, apoptosis (programmed cell death), and cellular senescence, in response to genomic damage and cellular or environmental stress. About half of all human cancers carry mutant p53, making p53 the most commonly mutated protein in human cancers. Most p53 cancer mutants exhibit a single missense mutation, which results in full-length p53 protein with a single amino acid change (Olivier, et al., 2002, 2009).
Pharmaceutical reactivation of p53 cancer mutants (p53 “cancer rescue”) is a long-held goal of cancer therapy. The presence of full-length but mutated p53 in so many human cancers holds the promise of a novel cancer treatment strategy—small molecule drugs that favor or stabilize the wild-type conformation of p53, restore p53 function to cancer mutants, and reactivate p53 tumor suppressor pathways, thus shrinking or killing the tumor (Soussi & Beroud, 2001; Selivanova & Wiman, 2007; Sharpless & DePinho, 2007; Ventura, et al., 2007; Wiman, 2007; Xue, et al., 2007; Wang & El-Deiry, 2008; Brown, et al., 2009).
1.1. Challenges Facing Pharmaceutical Reactivation of p53 Cancer Mutants.
Challenges are summarized succinctly by a passage from a recent (2010) review article:                “In contrast to stimulating wt-p53 function, reactivation of a mutant and inactive protein as a therapeutic strategy might appear insurmountable if not naïve.” (Maslon & Hupp, 2010, p. 549).        
Challenges include: (1) a diverse variety of p53 cancer mutants and mechanisms; (2) the marginal stability of p53 at physiological temperatures; (3) insufficient understanding of p53 dynamics or flexibility; (4) elusive knowledge about the precise molecular mechanisms that reactivate p53 cancer mutants; (5) a paucity of p53 reactivation drug leads; (6) the novelty and difficulty of designing drugs to stabilize protein conformation instead of to modulate enzyme or signaling activity; and (7) a lack of sophisticated computational analysis tools to guide p53 biological and pharmaceutical discovery.
1.2. Current Small Molecule Approaches that Target p53 Reactivation.
Small molecule approaches that target p53 reactivation fall into several classes, including: (1) approaches that appear to intercalate small molecules into DNA, or otherwise cause DNA damage or DNA conformational change, and thereby perhaps increase the activation stimulus acting on p53 (Kohn, et al., 1975; Ross, et al., 1978; Foster, et al., 1999; Demma, et al., 2004; Reha, et al., 2002; Rippin, et al., 2002; Peng, et al., 2003; Canals, et al., 2005; Peltonen, et al., 2010); (2) approaches that appear to employ peptides or peptide-mimetics that bind to p53 (Selivanova, et al., 1997; Friedler, et al., 2002, 2004; Issaeva, et al., 2003); (3) approaches that appear to employ small molecules that bind covalently to p53 via cysteine alkylation (Bykov, et al., 2002, 2005; Beraza & Trautwein, 2007; Zache, et al., 2008; Lambert, et al., 2009; Kaar, et al., 2010; Karimi, et al., 2010); (4) approaches that appear to employ small molecules that bind non-covalently to p53 (Yu, et al., 2012; Zhao, et al., 2010ab); and (5) approaches that appear to employ small molecules or peptides that block p53 proteolysis or otherwise interact with p53 binding partners and so increase p53 protein abundance or activity (Wang, et al., 2005; Hara, et al., 2006; Vassilev, et al., 2004; Oltersdorf, et al., 2005; Kravchenko, et al., 2008; Shangary, et al., 2009; Demma, et al., 2010). However, these categories are often uncertain, imprecise, or overlapping.